Host determinants of susceptibility to Mycobacterium tuberculosis: the role of the biological sex

男性的结核病患病率明显高于女性。性别因素和与性别有关的因素都可能导致男性结核病发病率较高，但后者的作用在很大程度上被忽视了。我们实验室的研究表明，与雌性小鼠相比，雄性C57BL/6小鼠对结核分枝杆菌(Mtb)H37Rv的易感性增加，表现为疾病进展加快和过早死亡。男性的过早死亡与肉芽肿性病变的质量在性别之间的显著差异有关。异位淋巴结构，在小鼠和人类中与结核病保护相关，在男性中要小得多。与此相一致，CXCL13(通过协调表达CXCR5的淋巴细胞归巢到滤泡区而参与淋巴新生)和IL-23(在结核分枝杆菌感染期间刺激CXCL13表达)在男性肺中的表达显著降低。因此，我们的数据表明，感染结核分枝杆菌H37Rv后，男性肺部异位淋巴结构的形成受到损害。H37Rv不是目前相关的Mtb流行毒株，但北京血统的毒株正在全球范围内出现。在免疫学上，H37Rv和HN878的一个重要区别是诱导IL-17反应。HN878是研究最深入的北京分离株。IL-17不仅介导了对HN878的早期保护作用，而且通过诱导CXCL13来指导T细胞在肺淋巴滤泡内的定位，在疫苗诱导的抗结核免疫中发挥了关键作用。感染HN878后，男性死于感染的时间明显早于女性。值得注意的是，与女性相比，男性的IL-17A表达显著减少，淋巴滤泡要小得多。睾丸激素被描述为下调IL-17的产生和减弱Th17的反应。因此，我们假设，睾酮通过干扰淋巴滤泡形成的关键免疫途径，从而损害结核分枝杆菌感染的控制，从而促进男性结核病的发展。这项建议的主要目的是确定睾酮对结核分枝杆菌保护性免疫反应的影响。具体地说，我们将研究其对IL-17A产生和HN878感染后异位淋巴结构形成的潜在抑制作用。此外，我们将调查男性和女性对结核病易感性的差异是否会转化为女性更好的疫苗诱导保护，以及我们是否可以通过联合雄激素剥夺治疗来提高男性的疫苗效力。这项研究的结果将显示与淋巴滤泡形成相关的分子通路如何在性别之间受到不同的调节，以及对结核杆菌感染肺中保护性免疫反应的发展和维持的影响。这一认识可能对设计新的疫苗策略以充分保护两性在未来感染结核杆菌具有深远的影响。

TB prevalence is significantly higher among men than women. Both gender- and sex-related factors likely contribute to higher Tb rates in men but the role of the latter has been largely ignored. Studies in our lab revealed an increased susceptibility of male C57BL/6 mice towards Mycobacterium tuberculosis (Mtb) H37Rv, reflected by accelerated disease progression and premature death compared to females. Premature death of males was associated with striking differences in the quality of the granulomatous lesions between the sexes. Ectopic lymphoid structures, associated with protection in Tb in mice and man, were much smaller in size in males. In line with this, expression of CXCL13, which is involved in lymphoid neogenesis by orchestrating the homing of CXCR5 expressing lymphocytes to the follicular areas, and IL-23 which stimulates CXCL13 expression during Mtb infection were significantly lower in the male lung. Hence, our data indicate impaired formation of ectopic lymphoid structures upon infection with Mtb H37Rv in male lungs. H37Rv is not a relevant Mtb circulating strain today but strains of the Beijing lineage are emerging worldwide. Immunologically one important difference between H37Rv and HN878, the best studied Beijing isolate, is the induction of IL-17 responses. IL-17 not only mediates early protection against HN878 but also has a critical role in vaccine-induced immunity against Tb via the induction of CXCL13 to instruct the localization of T cells within lung lymphoid follicles. Upon HN878 infection, males succumbed to infection significantly earlier than females. Of note, IL-17A expression was significantly reduced and lymphoid follicles were much smaller in males compared to females. Testosterone has been described to downregulate the production of IL-17 and to attenuate Th17 responses. Therefore we hypothesize that testosterone promotes Tb disease development in males by interfering with this critical immune pathway involved in lymphoid follicle formation, thereby impairing control of Mtb infection. The main objective of this proposal is to determine the effect of testosterone on protective immune responses to Mtb. Specifically; we will investigate its potential inhibitory effect on IL-17A production and the formation of ectopic lymphoid structures upon HN878 infection. Moreover, we will investigate whether the difference in susceptibility to Tb in males and females translates into superior vaccine induced protection in females, and if we can enhance vaccine efficacy in males by combined androgen-deprivation therapy. Findings from this research will show how molecular pathways associated with lymphoid follicle formation are differently regulated between the sexes and impact on the development and maintenance of protective immune responses in the Mtb-infected lung. This understanding may have far reaching implications for the design of novel vaccine strategies to adequately protect both sexes against Mtb in the future.